Topoisomerases are nuclear enzymes that play an essential role in DNA metabolism and have emerged as the receptors for several clinically important anticancer agents. This proposal describes a research program directed toward the chemistry and biology of two classes of natural products that exhibit excellent antitumor activity by "poisoning" topoisomerase II. With a combination of bioorganic, computational and biological studies we aim to elucidate the mode of action of the above compounds and address issues pertaining to their structure-activity relationship. Research along these lines is expected to aid in the development of powerful and selective anticancer agents and could have important implications for cancer treatment.